FoxP3+ T Cells Undergo Conventional First Switch to Lymphoid Tissue Homing Receptors in Thymus but Accelerated Second Switch to Nonlymphoid Tissue Homing Receptors in Secondary Lymphoid Tissues

Abstract

Forkhead box P3 (FoxP3)-positive T cells are a specialized T cell subset for immune regulation and tolerance. We investigated the trafficking receptor switches of FoxP3⁺ T cells in thymus and secondary lymphoid tissues and the functional consequences of these switches in migration. We found that FoxP3⁺ T cells undergo two discrete developmental switches in trafficking receptors to migrate from primary to secondary and then to nonlymphoid tissues in a manner similar to conventional CD4⁺ T cells as well as unique to the FoxP3⁺ cell lineage. In the thymus, precursors of FoxP3⁺ cells undergo the first trafficking receptor switch (CCR8/CCR9→CXCR4→CCR7), generating mostly homogeneous CD62L⁺CCR7⁺CXCR4^lowFoxP3⁺ T cells. CXCR4 expression is regained in FoxP3⁺ thymic emigrants in the periphery. Consistent with this switch, recent FoxP3⁺ thymic emigrants migrate exclusively to secondary lymphoid tissues but poorly to nonlymphoid tissues. The FoxP3⁺ thymic emigrants undergo the second switch in trafficking receptors for migration to nonlymphoid tissues upon Ag priming. This second switch involves down-regulation of CCR7 and CXCR4 but up-regulation of a number of memory/effector type homing receptors, resulting in generation of heterogeneous FoxP3⁺ T cell subsets expressing various combinations of trafficking receptors including CCR2, CCR4, CCR6, CCR8, and CCR9. A notable difference between the FoxP3⁺ and FoxP3⁻ T cell populations is that FoxP3⁺ T cells undergo the second homing receptor switch at a highly accelerated rate compared with FoxP3⁻ T cells, generating FoxP3⁺ T cells with unconventionally efficient migratory capacity to major nonlymphoid tissues.